title: Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism.
abstract: Leprechaunism is the most severe form of insulin resistance, manifesting with abnormal glucose metabolism and retarded growth. In the present study, we investigated the biological actions of recombinant human insulin-like growth factor I (rhIGF-I) in fibroblasts derived from a patient with leprechaunism. In the same patient, we also investigated the pharmacokinetics of IGF-I and the long-term effect of rhIGF-I treatment on metabolic control and physical growth. The patient's fibroblasts showed normal binding of IGF-I, normal phosphorylation of the beta-subunit of the IGF-I receptor, and normal [3H]thymidine incorporation in response to IGF-I. The fibroblast studies suggested that the patient would respond to IGF-I therapy, but certainly did not exclude the possibility of IGF-I resistance in vivo. Administration of recombinant human GH at the dose of 2.0 IU/kg for 3 consecutive days induced a minimal response of serum total IGF-I and IGF-binding protein-3 (IGFBP-3), suggesting partial GH resistance. To increase the serum total IGF-I level, we administered rhIGF-I with combination therapy of intermittent and continuous s.c. injection. This sustained the serum total IGF-I level, but not the serum IGFBP-3 level, within the normal range. The patient was treated with combination therapy of rhIGF-I by both s.c. injection and continuous s.c. infusion for 6 yr and 10 months. Administration of rhIGF-I at total daily dose of 1.6 mg/kg maintained her growth rate and hemoglobin A1c level nearly within the normal range. These findings suggest 1) that this leprechaun patient has an IGF-I-deficient state and partial GH resistance, as reflected by impaired production of IGF-I and IGFBP-3; 2) that rhIGF-I treatment works effectively for preventing postnatal growth retardation and normalizing glucose metabolism in patients with extreme insulin resistance; 3) that this treatment requires relatively higher dose of rhIGF-I; and 4) that treatment appears to be safe and devoid of adverse effects.
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Nakae
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.forename: M
authors.initials: M
authors.lastname: Murashita
authors.forename: N
authors.initials: N
authors.lastname: Shinohara
authors.forename: T
authors.initials: T
authors.lastname: Tajima
authors.forename: K
authors.initials: K
authors.lastname: Fujieda
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D004247:DNA / Q000096:biosynthesis; D004351:Drug Resistance; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006128:Growth; D006130:Growth Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D007564:Japan; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D004247:DNA; D017526:Receptor, IGF Type 1